Proportion of carriers of the minor allele according to age in controls free of neurological disease.

<p>SNP = single nucleotide polymorphism. CI = confidence interval. *Chromosomal positions based on the February 2009 (GRCH37/hg19) genome assembly [<i>SNCA</i> is located at Chr4;90,645,251–90,759,447]. P-values result from logistic regression models adjusted for gender, where the outcome was presence of the minor allele of the given SNP, and the predictor variable was age as a continuous variable. Genotype call rates for all SNPs were >95%.</p

Linkage disequilibrium between SNPs in controls as measured by pairwise r² values.

<p>Values are given as percentages out of a maximum of 100. Solid black boxes indicate an r² value of 100.</p

Single SNP associations with PD.

<p>PD = Parkinson's disease. SNP = single nucleotide polymorphism. MA = minor allele. OR = odds ratio. CI = confidence interval. *Chromosomal positions based on the February 2009 (GRCH37/hg19) genome assembly [<i>SNCA</i> is located at Chr4;90,645,251–90,759,447]. ORs, 95% CIs, and p-values result from logistic regression models adjusted for age and gender. ORs correspond to presence vs. absence of the minor allele.</p

Bilateral small chronic infarcts and patchy and confluent areas of leukoaraiosis seen on fluid attenuated inversion recovery (FLAIR) MRI on patient with NOTCH3 p.R558C mutation.

<p>Bilateral small chronic infarcts and patchy and confluent areas of leukoaraiosis seen on fluid attenuated inversion recovery (FLAIR) MRI on patient with NOTCH3 p.R558C mutation.</p

Exonic Re-Sequencing of the Chromosome 2q24.3 Parkinson’s Disease Locus

<div><p>Genome-wide association studies (GWAS) in Parkinson’s disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: <i>B3GALT1</i>, <i>STK39</i>, and <i>CERS6</i>. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels). These non-synonymous variants and rs2102808, the GWAS tag SNP, were genotyped in three independent series consisting of a total of 1976 patients and 1596 controls. Our results show that the seven identified 2q24.3 coding variants are not independently responsible for the GWAS association signal at the locus; however, there is a haplotype, which contains both rs2102808 and a <i>STK39</i> exon 1 6bp indel variant, that is significantly associated with PD risk (Odds Ratio [OR] = 1.35, 95% CI: 1.11–1.64, P = 0.003). This haplotype is more associated than each of the two variants independently (OR = 1.23, P = 0.005 and 1.10, P = 0.10, respectively). Our findings suggest that the risk variant is likely located in a non-coding region. Additional sequencing of the locus including promoter and regulatory regions will be needed to pinpoint the association at this locus that leads to an increased risk to PD.</p></div

Single variant associations with PD.

<p>MAF = minor allele frequency, OR = Odds ratio, CI = confidence interval, P = p-value, P corr = p-value with Bonferroni correction. ORs, 95% CIs, and P-values result from logistic regression models adjusted for age, gender, and series (combined series only).</p><p>*Numbers of samples with complete clinical information included in model.</p><p>Single variant associations with PD.</p

Haplotypic associations with PD.

<p>Haplotypes are encoded as 1 for major allele and 2 for minor allele see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128586#pone.0128586.t002" target="_blank">Table 2</a> for specific alleles, MAF = minor allele frequency, OR = Odds ratio, CI = confidence interval, P = p-value, P corr = P-value with Bonferroni correction. ORs, 95% CIs, and P-values result from haplotype-based logistic regression analysis.</p><p>*Numbers of samples with complete clinical information included in model.</p><p>Haplotypic associations with PD.</p

Exonic variants detected by sequencing of 187 PD patients and validation in 376 controls.

<p>*Exon 1 of <i>B3GALT1</i> is non-coding, AA = amino acid, MAF = minor allele frequency, OR = Odds ratio, CI = confidence interval, P = P-value. Only non-synonymous and indel coding variants were genotyped in controls.</p><p>Exonic variants detected by sequencing of 187 PD patients and validation in 376 controls.</p

Patient characteristics.

<p>The sample mean ± SD (minimum-maximum) is given for age and age at onset.</p><p>Patient characteristics.</p

<i>STK39</i> exon 1 insertion/deletion variants.

<p>We detected three insertion/deletion (indels) variants in exon 1 of gene <i>STK39</i>. The indels are located in a proline/alanine rich protein domain called the PAPA box. The figure was created using the UCSC genome browser. (<a href="http://genome.ucsc.edu/" target="_blank">http://genome.ucsc.edu/</a>)</p